Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid β protein (Aβ) in brain regions serving memory and cognition. In animal models of AD, immunization with Aβ results in the clearance of Aβ deposits from the brain. However, a trial of vaccination with synthetic human Aβ1–42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Aβ in middle-aged and elderly healthy subjects and in patients with AD. A significantly higher proportion of healthy elderly subjects and patients with AD had strong Aβ-reactive T cell responses than occurred in middle-aged adults. The immunodominant Aβ epitopes in humans resided in amino acids 16–33. Epitope mapping enabled the identification of MHC/T cell receptor (TCR) contact residues. The occurrence of intrinsic T cell reactivity to the self-antigen Aβ in humans has implications for the design of Aβ vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process.